This invention relates to a process for the manufacture of intermediates for .beta.-lactam antibiotics. In particular, it relates to an improved process for the manufacture of 7-substituted amino-3-hydroxy-3-cephem-4-protected carboxy sulfoxide esters.
The preparation of 3-exomethylenecepham sulfoxide esters is carried out by the known two-step process which comprises the conversion of a penicillin sulfoxide ester to a chlorosulfinylazetidinone followed by the cyclization of the latter to a 3-exomethylenecepham sulfoxide ester. The penicillin sulfoxide ester is converted to the intermediate chlorosulfinylazetidinone with an N-chloro halogenating agent as described by Kukolja in U.S. Pat. No. 4,165,315. The 4-chlorosulfinyl-azetidinone intermediates are described and claimed by Kukolja in U.S. Pat. No. 4,081,440. Chou, U.S. Pat. No. 4,075,203, describes the preparation of 3-exomethylene-cepham sulfoxide ester via conversion of the penicillin sulfoxide ester in step 1 to the 4-chlorosulfinylazetidinone with an N-chloro halogenating agent in the presence of an alkylene oxide and calcium oxide. Later, Chou, U.S. Pat. No. 4,289,695, describes an improved process for 3-exomethylenecepham sulfoxide esters by employing an acid scavenging cross-linked polyvinylpyridine polymer in step 1.
Kukolja, U.S. Pat. No. 4,052,387, describes the cyclization of 4-chlorosulfinylazetidinones with a Lewis acid-type Friedel-Crafts catalyst, a Bronsted proton acid-type Friedel-Crafts catalyst or with a metathetic cation-forming agent. Subsequently, Chou, U.S. Pat. No. 4,190,724, describes and claims an improved process which comprises carrying out the Kukolja Friedel-Crafts catalyzed cyclization of a 4-chlorosulfinylazetidinone in the presence of oxo compounds such as ethers, ketones or phosphine oxides. Copp et al., U.S. Pat. No. 4,950,753, incorporated herein by reference, describe a further improvement of the Kukolja process which comprises carrying out the Friedel-Crafts cyclization in the presence of both an oxo compound of Chou and an unsaturated compound e.g., an alkene such as 1- or 2-hexene, a non-conjugated alkadiene such as 1,4-hexadiene, a cycloalkene such as cyclohexene, an allene, or a non-conjugated cycloalkadiene such as 1,4-cyclohexadiene.
As taught by Kukolja, U.S. Pat. No. 4,052,387 and also by Chou, U.S. Pat. No. 4,190,724, a tin-containing complex is formed when using a tin-containing catalyst such as stannic chloride. The following illustrates such, and also the further processing applied to form the 3-exomethylenecephemsulfoxide, as taught by Chou: ##STR1## (R.sub.2 is a protected amino and R.sub.1 is a carboxy-protecting group).
In Scheme I, the 4-chlorosulfonylazetidinone (a) is combined with a tin-containing catalyst in an inert organic solvent to form a tin-containing complex intermediate. As noted in Chou U.S. Pat. No. 4,190,724, the complex may be isolated by filtering the reaction mixture, cooled, and stored for further use. An alternative, as shown in Scheme I, includes adding methyl alcohol to the reaction mixture to decompose the complex to provide the corresponding exomethylene cephamsulfoxide (c). Thereafter, as has been taught in the prior art, the 3-exomethylenecepham sulfoxide ester (c) is first isolated and then subjected to ozone to form 3-hydroxy-3-cephem-sulfoxide ester (d). The sulfoxide ester (d) may be reduced by known techniques, such as with phosphorus trichloride or phosphorus tribromide in DMF, to provide the 3-hydroxy-3-cephem ester, a useful intermediate in the production of antibiotics, such as cefaclor.
Heretofore it has been taught that the tin-containing complex had to be decomposed so that isolation of the 3-exomethylene sulfoxide ester could occur before further processing steps, such as ozonolysis, could be taken. However, the present invention affords a novel process which avoids the requirement of isolating the 3-exomethylene cepham sulfoxide ester prior to further processing, thus allowing a more efficient and streamlined process.